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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 2 729-733
Copyright © 2005 by The Endocrine Society

Orlistat Is as Beneficial as Metformin in the Treatment of Polycystic Ovarian Syndrome

V. Jayagopal, E. S. Kilpatrick, S. Holding, P. E. Jennings and S. L. Atkin

Department of Medicine (V.J., S.L.A.), University of Hull, Michael White Centre for Diabetes and Endocrinology, Hull Royal Infirmary, Hull HU3 2RW, United Kingdom; Department of Clinical Biochemistry and Immunology (E.S.K., S.H.), Hull Royal Infirmary, Hull HU3 2JZ, United Kingdom; and Department of Medicine (P.E.J.), York Hospital, York YO31 8HE, United Kingdom

Address all correspondence and requests for reprints to: Dr. V. Jayagopal, Department of Medicine, University of Hull, Michael White Centre for Diabetes and Endocrinology, Hull Royal Infirmary, Anlaby Road, Hull HU3 2RW, United Kingdom. E-mail: V.Jayagopal{at}hull.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The objective of this study was to evaluate and compare the effect of treatment with orlistat vs. metformin on the hormonal and biochemical features of patients with polycystic ovarian syndrome (PCOS).

Twenty-one Caucasian women with PCOS [mean (±SEM) age 27 ± 0.9 yr and body mass index 36.7 ± 3.3 kg/m2] participated in this prospective, randomized, open-labeled study. All subjects had an 8-wk run-in period of dietary modification and then randomized to receive either metformin (500 mg three times daily) or orlistat (120 mg three times daily) for 3 months. Weight, blood pressure, and fasting blood samples were taken at screening, randomization, and on completion. Insulin resistance (IR) was calculated using the homeostasis model of assessment (HOMA)-IR method [HOMA-IR = (insulin x glucose)/22.5].

The results are expressed as mean ± SEM. When compared with baseline, treatment with both orlistat [93.5 ± 11.5 ng/dl (3.24 ± 0.4 nmol/liter) vs. 114.5 ± 11.5 ng/dl (3.97 ± 0.4 nmol/liter), P = 0.039] and metformin [97.2 ± 11.5 ng/dl (3.37 ± 0.4 nmol/liter) vs. 120.0 ± 8.7 ng/dl (4.16 ± 0.3 nmol/liter), P = 0.048] produced a significant reduction in total testosterone. Treatment with orlistat produced a 4.69% reduction in weight (99.0 ± 6.0 vs. 94.6 ± 6.1 kg, P = 0.002), and this reduction was more significant than the reduction produced by metformin (4.69 vs. 1.02%, P = 0.006). There was no significant reduction seen after either treatment group for fasting insulin, HOMA-IR, SHBG, or any of the lipid parameters studied.

In this study, orlistat produced a significant reduction in weight and total testosterone. The reduction in total testosterone was similar to that seen after treatment with metformin. Therefore, orlistat may prove to be a useful adjunct in the treatment of PCOS.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
POLYCYSTIC OVARY SYNDROME (PCOS) is a common disorder of women of reproductive age and is characterized by chronic anovulation and androgen excess with the clinical manifestation of oligomenorrhoea, hirsutism, and acne (1, 2). Increased insulin resistance (IR) has been shown to be an important feature in PCOS and may contribute to the reported increased risk of developing type 2 diabetes and the adverse cardiovascular risk profile that is known to be present (3, 4). Hyperinsulinemia may contribute to the androgen excess seen and may be an important factor in the infertility associated with PCOS (5, 6, 7, 8). This association among IR, the metabolic syndrome, and androgen excess has led to the use of insulin-sensitizing agents such as metformin (9) and troglitazone (10) with reported improvements in hyperinsulinemia and hyperandrogenemia. Treatment with metformin and troglitazone, however, only produced a modest reduction in weight and hirsutism in women with PCOS (11, 12).

Obesity is present in varying degrees in women with PCOS (ranging from 10 to 50%) and is associated with reproductive dysfunction (13, 14). Improvements of IR through diet and exercise-induced weight loss have shown both clinical and metabolic improvements in some studies. Even modest weight loss (<10% of initial body weight) has been shown to increase the frequency of ovulation, improve conception, and reduce testosterone, hyperlipidemia, hyperglycaemia and IR in women with PCOS (15, 16, 17, 18, 19, 20). The combination of a low-calorie diet and treatment with metformin in women with PCOS has previously been shown to produce some differential effects. A low-calorie diet produced a similar reduction in weight in both PCOS and controls, but the addition of metformin to the diet produced greater weight reduction and a more significant reduction in visceral obesity and glucose-stimulated insulin release than in the group treated with diet and placebo (21).

Orlistat is a potent and irreversible inhibitor of gastric and pancreatic carboxylester lipase, inhibiting the digestion of dietary triglycerides and decreasing the absorption of lipids. Previous studies have shown that it produces significant and sustained weight loss with associated improvement in lipid parameters and carbohydrate metabolism (22, 23, 24, 25). Weight- reducing agents such as orlistat and sibutramine have additionally been shown to augment the effects of lifestyle modification in reducing the incidence of type 2 diabetes (26) and improve glycemic control in individuals with type 2 diabetes (27).

The benefit of orlistat in PCOS has not been demonstrated before, and this study in subjects with PCOS was therefore conducted to compare and contrast the change in testosterone and other metabolic parameters seen after treatment with orlistat to the changes seen after treatment with metformin.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Subjects

The study was approved by the Hull and East Riding Local Research Ethics committee, and all subjects gave written informed consent before entry into the study. Subjects were recruited over a 3-month period from the Hull Royal Infirmary Endocrinology outpatient clinic where they were referred by their primary care physicians for investigation of menstrual abnormalities, with or without hirsutism. Subjects were included in the study if they were diagnosed to have PCOS, had no concurrent illness, were not taking any medication currently or for the preceding 6 months, had not previously been pregnant and were not currently planning to conceive. The diagnosis of PCOS was based on evidence of hyperandrogenaemia (free androgen index > 8) with a history of oligomenorrhoea (cycle length, <21 d or >35 d; <8 cycles per year) or amenorrhea and hirsutism (Ferriman-Gallwey score > 8) (28). Nonclassical 21-hydroxylase deficiency, hyperprolactinemia, Cushing’s disease and androgen-secreting tumors were excluded by appropriate tests before the diagnosis of PCOS was made. Exclusion criteria included: inability to comply with study requirements, the presence of impaired fasting glycemia [fasting venous glucose ≥ 107 mg/dl (6.0 mmol/liter)], current or previous (in the preceding 6 months) use of estrogen therapy, untreated hypothyroidism, history of drug or alcohol abuse and a history of breast or uterine cancer. Thirty Caucasian women with PCOS were screened, and 21 were found suitable for inclusion. The 9 subjects excluded were due to 4 currently wishing to conceive, 2 having impaired fasting glycemia [fasting venous glucose ≥ 107 mg/dl (6.0 mmol/liter)], 2 having hyperprolactinemia, and 1 having undiagnosed hypothyroidism. For those included, the mean (± SEM) age was 27 ± 0.9 yr (range, 22 to 37). Their mean body weight was 96.2 ± 3.1 kg, and the mean body mass index (weight in kilograms divided by the square of the height in meters) was 36.7 ± 3.3.

Study design

A randomized, open-labeled, parallel study comparing treatment with metformin or orlistat for 3 months was undertaken. After initial screening, all women began with an 8-wk run-in period which started after receiving dietary advice from a registered dietician. All subjects were prescribed a weight maintenance diet containing approximately 30% of calories from fat, 50% as carbohydrate, and 20% as protein, with a maximum of 300 mg/d of cholesterol. Dietary compliance (using dietary diaries) was checked and dietary advice reinforced 4 wk after the initial consultation. The dietary assessment was later repeated at randomization and at the end of the study. At the end of the run-in phase, the women were randomized to treatment of either metformin or orlistat. The randomization was performed using pairs of sealed envelopes prepared in advance of the study by a research associate not involved in this study. The envelopes were paired so as to minimize chance imbalance. The envelopes contained slips of paper labeled M (metformin) or O (orlistat) and prepared in random order for M/O or O/M (29). The first two subjects randomized included one subject randomized to one of the two treatments and the other to the alternative. All subsequent pairs of subjects were randomized in similar fashion until the end of the 3-month recruitment period to ensure an equal number of subjects in each arm of the study.

The dose of metformin was in accord with a previous study showing the beneficial effect of metformin in PCOS (9) and increased step-wise, from 500 mg once daily for the first week to 500 mg twice daily for the next week, and to 500 mg three times daily for the remainder of the study period. The dose of orlistat was 120 mg three times daily before each meal. After randomization, the subjects were advised not to modify their eating habits throughout the study. Clinical and biochemical assessments were performed at randomisation and at the end of the 3-month period. The subjects attended an interim check 6 wk after start of medication for a compliance check and to record any side effects. The primary end points of the study were change in total testosterone and weight. The secondary outcome measures were change in fasting insulin, IR, SHBG, and lipid profile.

Study measurements

After an overnight fast, weight and blood pressure were measured and blood samples were taken at screening, randomization, and on completion of the 12-wk study period. Compliance was monitored based on counting returned medication. Fasting venous blood was collected into serum gel and fluoride oxalate tubes. Samples were separated by centrifugation at 2000 gfor 15 min at 4 C, and the aliquots stored at –20 C within 1 h of collection. Sitting blood pressure was measured after 10 min of rest using an automated device (NPB-3900, Nellcor Puritan Bennett, Pleasanton, CA).

Total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol levels were measured enzymatically using a Synchron LX20 analyzer (Beckman-Coulter, High Wycombe, UK). Low-density lipoprotein cholesterol was calculated using the Friedewald equation. Serum insulin was assayed using a competitive chemiluminescent immunoassay performed on the manufacturer’s DPC Immulite 2000 analyzer (Euro/DPC, Llanberis, UK). The analytical sensitivity of the insulin assay was 2 µU/ml, the coefficient of variation was 6%, and there was no stated cross-reactivity with proinsulin. Plasma glucose was measured using a Synchron LX 20 analyzer (Beckman-Coulter, High Wycombe, UK), using the manufacturer’s recommended protocol. The coefficient of variation for this assay was 1.2% at a mean glucose value of 94.6 mg/dl (5.3 mmol/liter) during the study period. The IR was calculated using the homeostasis model assessment (HOMA) method (HOMA-IR = (insulin x glucose)/22.5) (30). Serum testosterone was measured on an Architect analyzer (Abbott Laboratories, Maidenhead, UK), and SHBG was measured by immunometric assay with fluorescence detection on the DPC Immulite 2000 analyzer using the manufacturer’s recommended protocol. The free androgen index was obtained as the quotient 100 T/SHBG.

Statistical analysis and sample size calculation

The power of the study to demonstrate a significant reduction in total testosterone was based on a previous study showing a significant reduction in total testosterone concentration after treatment with metformin (9). Using two-sided 5% significance level, a sample of 10 patients per group was found to be needed (assuming a 20% dropout rate) to detect changes in total testosterone with 90% power. The effect of treatment was evaluated by first computing the percentage change from baseline in all variables studied and then the percentage change seen for each variable in both groups was compared, thus negating the differences in the baseline values of the two groups. Comparisons between the metformin group and the orlistat-treated group, with respect to percentage changes from baseline were carried out using the paired t test for biochemical data and the Wilcoxon signed rank test for the clinical observations. The Wilcoxon signed rank test was also applied to biochemical data that violated the assumptions of normality when tested using the Kolmogorov-Smirnov test.

For all analysis, a two-tailed P < 0.05 was considered to indicate statistical significance. Statistical analysis was performed using SPSS for Windows NT, version 9.0 (SPSS Inc., Chicago, IL), and nQuery version 4 was used for sample size determination.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
All 21 subjects included completed the 3-month study period. Eleven women were randomized to receive metformin treatment and 10 were randomized to receive orlistat. The compliance was 93% in the metformin-treated group and 88% in the orlistat-treated group. Four subjects given metformin reported having mild nausea (4), heartburn (2), and mild abdominal pain (1). These symptoms resolved within 4 wk, and no subject required any dose reduction. Two subjects given orlistat reported mild to moderate flatulence and oily stools intermittently during the study period. Subject characteristics at the start and after 12-wk treatment with metformin and orlistat are shown in Table 1Go. Data are presented as mean ± SEM.


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  		TABLE 1. Subject characteristics at the start and after 12-wk treatment

 
Weight

The 8-wk run-in period of dietary stabilization did not produce a significant change in weight in either the metformin group (94.1 ± 3.1 vs. 93.6 ± 3.2 kg, P = 0.119) or the orlistat group (99.4 ± 5.8 vs. 99.0 ± 6.0 kg, P = 0.359). Treatment with orlistat for 12 wk resulted in a 4.69% reduction in weight when compared with baseline (99.0 ± 6.0 vs. 94.6 ± 6.1 kg, P = 0.002). This reduction in weight aftertreatment with orlistat was more significant than the reduction in weight seen in the metformin-treated group (4.69% vs. 1.02%, P = 0.006).

In the orlistat-treated group, 9 of the 10 women showed a reduction in weight after treatment (range, 1.8% to 11.7% reduction in weight), and one subject showed a 0.2% increase in weight. In the metformin-treated group, 7 subjects showed a reduction in weight (range, 1.0% to 8.3% reduction in weight), and 4 subjects showed an increase in weight after treatment (range, 0.8% to 3.0% increase in weight).

Testosterone and SHBG

Figure 1Go shows the change in testosterone after 12 wk of treatment for both treatment groups. When compared with baseline, a significant reduction in serum testosterone was observed post treatment in both the orlistat-treated group [93.5 ± 11.5 ng/dl (3.24 ± 0.4 nmol/liter) vs. 114.5 ± 11.5 ng/dl (3.97 ± 0.4 nmol/liter), P = 0.039] and the metformin- treated group [97.2 ± 11.5 ng/dl (3.37 ± 0.4 nmol/liter) vs. 120.0 ± 8.7 ng/dl (4.16 ± 0.3 nmol/liter), P = 0.048]. There was no significant change in SHBG concentration post treatment in either treatment group.



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  		FIG. 1. Mean (SEM) change in testosterone concentration (ng/dl) after 12 wk of treatment for both treatment groups. To convert values for testosterone to nmol/liter, multiply by 0.03467.

 
IR

In the orlistat-treated group when compared with baseline, there was no significant reduction seen in fasting insulin [15.7 ± 8.0 µIU/ml (94.2 ± 48 picomoles/liter) vs. 19.0 ± 4.6 µIU/ml (114 ± 27.6 picomoles/liter), P = 0.155] or HOMA-IR (3.58 ± 0.7 vs. 4.32 ± 1.2 U, P = 0.196).

When compared with baseline, in the group treated with metformin there was similarly no significant reduction in fasting insulin [18.2 ± 2.6 µIU/ml (109.2 ± 15.6 picomoles/liter) vs. 19.4 ± 2.6 µIU/ml (116.4 ± 15.6 picomoles/liter), P = 0.527] or HOMA-IR (4.09 ± 0.7 vs. 4.27 ± 0.6 U, P = 0.693).

There was no statistical difference in comparison between the two treatments for the change in either fasting insulin (P = 0.426) or HOMA-IR (P = 0.756).

Lipids

There was no significant improvement in any of the lipid parameters studied in either treatment group. In addition there was no difference in the comparison between the two treatment groups in any of the lipid parameters.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Metformin therapy to ameliorate the hormonal and metabolic consequences of PCOS is now regarded as acceptable practice (31, 32). This study in women with PCOS aimed to contrast and compare the metabolic changes that follow treatment with orlistat to that seen after treatment with metformin.

As expected, the subjects treated with orlistat had a significantly greater degree of weight loss than those treated with metformin. The group treated with orlistat was also found to have a significant reduction in testosterone concentration, which is consistent with previously reported reduction in testosterone in overweight individuals with PCOS after weight reduction by dietary modification and exercise (17, 18, 33). In keeping with previously reported (9) changes after treatment with metformin in PCOS, a small reduction in weight was noted although the reduction in weight was much less than that seen in the orlistat-treated group. Despite this difference in weight reduction however, the metformin- treated subjects also showed a similar reduction in testosterone concentration to the group treated with orlistat, and this is consistent with the known beneficial effect of metformin in PCOS (9, 34).

Weight reduction in PCOS has also been reported to improve hyperlipidemia, reduce IR, and increase SHBG concentration, thereby reducing biochemical hyperandrogenism and improving menstrual cyclicity (16, 17, 35, 36). Treatment with orlistat here produced no significant change in fasting insulin concentration, HOMA-IR, or SHBG concentration. The HOMA model is a validated technique of assessing IR (30), and studies comparing it to other measures of IR such as clamp studies have shown it to be a good measure of IR (37, 38). It is however known that individuals with PCOS show a large variability in their HOMA-IR readings (39). In studies with a large sample, this variation will not have a significant influence on the result, but the results of smaller studies may well be limited by the wide spread of HOMA-IR values. The lack of statistically significant improvement in IR in this study may in part be due to the large variability in HOMA-IR values, and this can be overcome in the future studies by using a larger study sample.

Treatment with orlistat produced no significant change in the lipid parameters studied despite a reduction in weight, and this is also likely to be due to the study not being powered to assess this change. The lack of change in the lipid parameters after treatment with metformin is similar to the effects seen in a previous report (9) where the only improvement seen was a rise in HDL cholesterol after treatment with metformin.

An interesting aspect of the changes observed in this study is that, in many of the endocrine and metabolic parameters studied, the change seen in terms of percentage change from baseline was more marked in the orlistat-treated group, perhaps suggesting that weight reduction had an overall stronger impact on these parameters than the insulin-sensitizing effect of metformin, the mechanism of which remains largely unknown. Orlistat inhibits triglyceride and lipid absorption and has been shown to reduce serum lipid concentrations, but its effect on reversing fatty liver disease has not been studied and may offer a mechanism for the reduction fasting insulin that has been shown to occur after treatment (23).

Improvement in menstrual irregularities and ovulation after weight reduction and treatment with insulin-sensitizing agents such as metformin has been previously documented (17, 18, 19, 20, 40). Information on the relative efficacy of orlistat and metformin in improving menstrual irregularities and ovulation is clearly important as it may influence an individual’s choice of treatment if fertility is desired. Information regarding menstrual change and ovulation was not collected in this study as the study was not powered to address this change and we felt the relatively short intervention period would limit any conclusions that could be offered.

In conclusion, this study has demonstrated the therapeutic potential of orlistat in PCOS by producing weight loss and a reduction in testosterone concentration. The improvement seen after treatment with orlistat was additionally similar to that seen with metformin, reaffirming the potential for orlistat to be a useful adjunct in the treatment of PCOS.


   Footnotes
 
First Published Online November 9, 2004

Abbreviations: HOMA, Homeostasis model of assessment; IR, insulin resistance; PCOS, polycystic ovarian syndrome.

This study was supported by an unrestricted educational grant from Roche Products, Ltd. (Welwyn Garden City, Hertfordshire, UK) and the Diabetes and Endocrinology Fund, Hull Royal Infirmary (Hull, UK).

Received February 3, 2004.

Accepted November 3, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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